Breast cancer trial: Dr Yap Yoon Sim on why ongoing clinical trial is significant for patients with PIK3CA-mutant, hormone receptor-positive, Her2-negative, locally advanced or metastatic breast cancer

The phase III, randomised, double-blind, placebo-controlled study evaluates the efficacy and safety of GDC-0077 plus palbociclib and fulvestrant versus placebo plus palbociclib and fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive, Her2-negative, locally advanced or metastatic breast cancer. It is being conducted across multiple locations in the Asia Pacific, Europe and North America, including Singapore’s National Cancer Centre and National University Hospital.

About the principal investigator: Assoc Prof Yap Yoon Sim, MBBS, FRACP, PhD, Senior Consultant, National Cancer Centre Singapore

Dr Yap is Senior Consultant in the Division of Medical Oncology at the National Cancer Centre Singapore, and Associate Professor at Duke-NUS Medical School. A recipient of the Singapore National Medical Research Council (NMRC) Clinician Scientist Award (CSA), her research focuses primarily on clinical and translational research in breast cancer, including liquid biopsies and predictive biomarkers, development of novel therapeutic strategies, and epidemiologic studies on treatment outcomes in breast cancer.

*Intended readers: healthcare and industry professionals

Tell us more about your ongoing trial. Why is it significant?

It is significant because while recent improvements and outcomes have been achieved with the use of CDK inhibitors in addition to endocrine therapy in women who have advanced hormone receptor-positive Her2-negative breast cancer, there are some patients who do not respond as well to the CDK inhibitors. Such patients may harbour PIK3CA mutations, and while using CDK inhibitors may be effective in the metastatic setting, the duration of disease control appears to be shorter than patients who do not harbour these mutations in the tumours.

Patients who relapse while still on adjuvant endocrine therapy or anti hormone treatment tend to have more aggressive refractory disease as opposed to those who relapse many years later after stopping the treatment. Hence combining GDC-0077, which is a PIK3CA inhibitor, with a CDK inhibitor and fulvestrant may potentially help to overcome this resistance to both the endocrine therapy and CDK inhibitors.

How common is the PIK3-CA mutation in breast cancer patients?

It’s estimated to be at about 30 per cent of the population of breast cancer patients, regionally, while some studies from the west point to a prevalence of 40 per cent. This means that a significant number of patients have these mutations in their breast cancers.

Who is eligible for the trial? Are there any unique requirements such as specific biomarkers/molecular profiles that are required for trial enrolment?

All patients must have shown evidence of the PIK3CA mutation either from their tumour or a liquid biopsy (plasma sample). This is a Phase 3 trial, where patients who have relapsed while on or within a year of stopping endocrine therapy in the adjuvant setting - with hormone receptive positive Her2-negative breast cancer - will receive fulvestrant, palbociclib and GDC-0077, or fulvestrant, palbociclib and placebo. Patients also have to be fit enough for trial enrolment, and have good organ and bone marrow function. The PI3K inhibitor can cause hyperglycemia, so patients must not have poorly controlled diabetes or glycated hemoglobin above a certain level.

What specific outcomes do you hope to achieve from this trial?

The primary end point of the trial is Progression Free Survival (PFS). Ultimately, we hope that it will also translate into an overall survival benefit as well as maintain the quality of life of breast cancer patients. since it may be better tolerated than the older PI3K inhibitors.

When was the trial started?

The trial was supposed to start around March, but was put on hold because of Covid-19. We began formally recruiting patients only in July.

What else should physicians and cancer patients take note of, with regard to this study?

The good thing about the trial is that it provides quite a comprehensive evaluation of the genomic profile of the tumour through FoundationOne testing, either through testing of the tumour specimen or a blood specimen for the circulating tumour DNA.

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*The content in this article is purely educational and written for healthcare professionals. It does not contain forward-looking statements, or those specific to commercial enterprise.